Avionco^® (Capsules) Instructions for Use

Marketing Authorization Holder

Newvac, LLC (Russia)

Manufactured By

Chemical Diversity Research Institute LLC (Russia)

ATC Code

L01XH (Histone deacetylase (HDAC) inhibitors)

Active Substance

Quisinostat (Prop.INN)

Dosage Forms

	Avionco®	Capsules 1 mg: 12 pcs.
		Capsules 5 mg: 12 pcs.

Dosage Form, Packaging, and Composition

Capsules

6 pcs. – blister packs (2 pcs.) – cardboard packs (12 pcs.) – By prescription

Capsules

6 pcs. – blister packs (2 pcs.) – cardboard packs (12 pcs.) – By prescription

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents; histone deacetylase (HDAC) inhibitors

Pharmacological Action

Quisinostat is an inhibitor of histone deacetylases HDAC1/HDAC6. Histone deacetylases are enzymes that catalyze the removal of an acetyl group from histones and some other protein substrates (heat shock protein Hsp90, tumor suppressor protein p53, tubulin).

Inhibition of histone deacetylases stimulates the acetylation of these proteins, which leads to changes in the expression of genes involved in proliferation, apoptosis, and differentiation. It has been shown that histone deacetylase inhibitors cause cell cycle arrest, terminal differentiation, or apoptosis of tumor cell lines in vitro and demonstrate antitumor activity in xenogeneic tumor models in vivo.

The antiproliferative effect of quisinostat is at least partially related to the induction of apoptosis of malignant cells. In preclinical in vitro studies, it caused the death of a wide range of tumor cell lines with IC50 in the range from 1.7 to 144 nM. The tumor genotype, in particular p53 or Rb protein mutations, did not affect the antiproliferative effect of the drug. Furthermore, the expression of P-glycoprotein by malignant cells, which provides multiple drug resistance of the tumor, does not prevent sensitivity to quisinostat, although it is a substrate of this protein transporter.

In vivo studies have shown pronounced antitumor activity of quisinostat against tumor xenografts, regardless of tissue origin or genotypic status.

Pharmacokinetics

After oral administration, Quisinostat is rapidly absorbed in the intestine, reaching C_max in 2-4 hours. The estimated permeability of quisinostat was low. However, this parameter depends on the pH values in the intestine: at high pH values, the permeability was higher. After a single dose and at steady state, the C_max and AUC values of quisinostat increase proportionally to the dose. With daily administration of a 12 mg dose, C_max averaged about 1.5 mg/ml. C_ss 24 hours after administration was approximately 6 times lower than C_max. With alternative dosing regimens, C_max and AUC values were slightly lower than with daily administration. Food intake does not have a significant effect on the AUC of quisinostat and has a minimal effect on C_max.

Quisinostat is characterized by high clearance and high V_d, indicating extensive distribution outside the blood plasma. Distribution in erythrocytes is low; high concentrations have been shown in the adrenal glands and lungs, while the level of the drug in the skin and brain was lower than in the blood plasma. The degree of binding of quisinostat to blood plasma proteins is concentration-dependent and ranges from 61.9% to 89.2%. Accumulation of the drug is absent or insignificant.

The main metabolic pathways of quisinostat are hydrolysis to an acid metabolite followed by glucuronidation, oxidation and N-demethylation, and reduction to an amide followed by oxidation, glucuronidation and N-demethylation. Minor metabolic pathways included oxidation and glucuronidation of the parent compound. The main isoenzymes involved in the oxidative metabolism of quisinostat are CYP3A4, CYP3A5 and CYP2C18.

C_max of the acid metabolite in blood plasma is reached 4-8 hours after administration; C_max and AUC values increase proportionally to the dose. At steady state, the metabolite concentration is 2 times higher than after a single dose, while C_max and AUC_0-24h are 3-4 times and 6-9 times higher, respectively, than the values obtained for the parent compound.

Quisinostat inhibits CYP2D6 (IC₅₀=4.50 µg/ml), does not inhibit or insignificantly inhibits other CYP isoenzymes at concentrations up to 100 µmol, mechanism-based inhibition was not noted. Induction of cytochrome P450 is absent or insignificant. According to in vitro data, fluconazole and erythromycin, when taken concomitantly, may inhibit the metabolism of quisinostat.

After reaching C_max, the concentration of quisinostat decreases according to a biphasic model. The primary elimination phase is short (T_1/2~2-3 hours), and the terminal elimination phase was shorter (T_1/2 ~22 hours). The effective half-life (T_1/2,eff) is 13-17 hours. The T_1/2 of the acid metabolite is higher than that of the parent compound. Elimination of quisinostat in feces is more significant than elimination in urine.

Indications

As part of combination therapy for the 2nd line: metastatic or locally advanced epithelial ovarian cancer resistant to first-line platinum-based chemotherapy; primary peritoneal carcinoma or fallopian tube carcinoma resistant to 1st-line platinum-based chemotherapy.

ICD codes

Dosage Regimen

Take orally in combination with other cytostatics (cisplatin and carboplatin).

Administer the recommended dose of 12 mg once daily according to a special schedule.

Adhere strictly to the prescribed schedule for administration and rest periods.

For individual dose selection, consult specialized literature and clinical guidelines.

Swallow capsules whole with water; do not chew or crush.

Take at approximately the same time each day to maintain steady plasma concentrations.

Dose adjustments may be necessary based on tolerability and clinical response.

Monitor for adverse reactions, particularly myelosuppression and QT interval prolongation.

Discontinue treatment if severe or life-threatening adverse events occur.

Adverse Reactions

Infections and infestations infrequently – wound infection, respiratory tract infections, bronchitis; frequency unknown – HIV-1 reactivation.

Blood and lymphatic system disorders very often – thrombocytopenia, neutropenia; often – anemia, leukopenia.

Cardiac disorders very often – ventricular tachycardia; often – cardiac disorders (T wave inversion, ST abnormalities or depression, QTc interval prolongation and Holter/ECG abnormalities, QTcF interval prolongation), atrial fibrillation, ventricular extrasystoles, QT interval (QTc) prolongation, supraventricular tachycardia, cardiac arrest due to ventricular fibrillation, arterial hypertension; infrequently – arterial hypotension, palpitations, heart failure, myocardial ischemia, atrial fibrillation, ventricular tachycardia, second-degree AV block, bradycardia, sinus arrhythmia.

Metabolism and nutrition disorders very often – decreased appetite.

Nervous system disorders often – lethargy, paresthesia, peripheral sensory neuropathy, neuralgia; infrequently – dysgeusia, insomnia, dizziness, hypesthesia.

Musculoskeletal and connective tissue disorders infrequently – myalgia, peripheral edema.

Respiratory, thoracic and mediastinal disorders often – dyspnea; infrequently – cough.

Gastrointestinal disorders very often – diarrhea, nausea; often – vomiting, abdominal pain, constipation.

Psychiatric disorders infrequently – memory impairment, irritability, affective disorder.

Hepatobiliary disorders infrequently – biliary colic, cholecystitis, cholelithiasis.

Skin and subcutaneous tissue disorders infrequently – alopecia, pruritus.

Renal and urinary disorders rarely – acute renal failure.

General disorders and administration site conditions often – fatigue, asthenia; infrequently – impaired healing; infrequently – pyrexia.

Investigations infrequently – increased troponin level, hyponatremia, hyperglycemia, hyperbilirubinemia, hypokalemia, hypoalbuminemia, increased blood alkaline phosphatase activity.

Contraindications

Hypersensitivity to quisinostat, pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Pediatric Use

The safety and efficacy of the drug in children under 18 years of age have not been established to date. Data are not available.

Special Precautions

If gastrointestinal disorders develop during therapy, including nausea, vomiting, and diarrhea, the administration of antiemetic and antidiarrheal agents may be required. To prevent dehydration and maintain electrolyte balance, rehydration and electrolyte replacement are recommended. If the patient has pre-existing nausea, vomiting, and diarrhea, they must be eliminated before starting treatment with quisinostat.

The antiemetic drug domperidone can lead to an increase in the QT (QTc) interval and induce arrhythmia – torsades de pointes ventricular tachycardia. In this regard, the concomitant use of quisinostat and domperidone should be avoided. It can only be used if other drugs are ineffective. In this situation, the benefit-risk ratio for the patient should be assessed, and ECG monitoring for QT (QTc) interval prolongation should be performed.

Therapy with quisinostat may be associated with the development of myelosuppression (anemia, neutropenia, leukopenia, and thrombocytopenia). Use with caution in patients with thrombocytopenia, leukopenia, neutropenia, and anemia with the following parameters: neutrophils ≥1.5×10⁹/L, platelets ≤100×10⁹/L, hemoglobin ≤90 g/L.

In case of treatment-induced myelosuppression, monitoring of white blood cells, platelets, hemoglobin, and neutrophils is necessary at least once a week. Recommended parameters before starting the next treatment cycle: white blood cell count and/or platelet count > 4×10⁹/L and > 100×10⁹/L, respectively.

Caution should be exercised when using quisinostat in patients with a history of arrhythmias or with factors predisposing to QT (QTc) interval prolongation, with uncontrolled or severe cardiovascular diseases, including recently suffered myocardial infarction, congestive heart failure, unstable angina, taking medications that can cause QT (QTc) interval prolongation (for example, antiarrhythmic drugs and other substances that can cause QT (QTc) interval prolongation). Hypokalemia and hypomagnesemia may exacerbate this effect.

It is recommended to perform an ECG study before starting therapy, as well as periodically during therapy for QT (QTc) interval prolongation. Hypokalemia and hypomagnesemia must be corrected before starting therapy, and during therapy, plasma potassium and magnesium concentrations should be periodically monitored.

In patients with significant risk factors, for example, with hypokalemia or congenital QT (QTc) interval prolongation, the use of drugs that can prolong the QT (QTc) interval should be avoided.

Studies showing that Quisinostat stimulates HIV-1 replication have not been conducted. However, it should be considered that various HDAC inhibitors reactivate latent HIV-1 in various experimental systems and in cells of HIV-infected people. Latent HIV-1 persists in CD4(+) T cells in infected patients receiving antiretroviral therapy. The delay is associated with suppression of integrated provirus transcription and is due, at least in part, to histone deacetylases (HDAC), which regulate histone acetylation and DNA accessibility to transcription factors. Notably, inhibition of HDAC is sufficient to reactivate part of the latent HIV-1 in various experimental systems.

These data should be considered when interpreting the results of continuous viral load monitoring in HIV-infected patients taking Quisinostat. Before starting treatment, patients with positive HIV-1 serology (including those with active disease) should consult with specialists in this disease. During treatment, patients are subject to observation and appropriate treatment.

The use of quisinostat, like other chemotherapeutic drugs, may predispose to the development of bacterial, fungal, viral, or protozoal infections due to the myelosuppressive effect.

Concomitant use of cyclosporine, ketoconazole, verapamil, quinidine, tacrolimus, and reserpine with quisinostat is not recommended.

Effect on ability to drive vehicles and operate machinery

Some adverse reactions, such as lethargy, dizziness, asthenia, and fatigue, may negatively affect the ability to drive vehicles or perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions. In case of the aforementioned adverse reactions, one should refrain from driving vehicles and operating machinery.

Drug Interactions

Quisinostat has been identified as a PgP substrate. Available data do not suggest any clinical consequences of this fact. Concomitant use of the following strong PgP inhibitors with quisinostat is not recommended: cyclosporine, ketoconazole, verapamil, quinidine, tacrolimus, and reserpine.

According to in vitro data obtained from human liver microsomes and heterologous expression systems, Quisinostat is mainly metabolized by CYP3A4, 3A5, and 2C18. Given the currently noted dose-dependent undesirable reactions from the cardiovascular system that occur at low plasma concentrations of quisinostat, enhancement of the drug’s effect due to drug-drug interaction is possible. Therefore, concomitant use of strong inhibitors of CYP3A4/A5 and CYP2C18 with quisinostat is not recommended. Such drugs include: macrolide antibiotics such as clarithromycin, telithromycin, troleandomycin, and erythromycin.

According to in vitro data, fluconazole and erythromycin may inhibit the metabolism of quisinostat when taken concomitantly with other drugs.

Quisinostat should not be used concomitantly with other histone deacetylase inhibitors (in particular, valproic acid, vorinostat) due to the predicted summation of side effects characteristic of this class of drugs.

With concomitant use of quisinostat and coumarin anticoagulants, in rare cases, patients experienced an increase in INR. If concomitant treatment with quisinostat and coumarin derivatives is necessary, careful monitoring of blood coagulation parameters is recommended.

Caution should be exercised when using quisinostat in patients who have or may have QT (QTc) interval prolongation, including patients who are receiving antiarrhythmic drugs such as amiodarone, disopyramide, procainamide, quinidine, and sotalol or other drugs that can lead to QT (QTc) interval prolongation (for example, chloroquine, halofantrine, clarithromycin, domperidone, haloperidol, pimozide, bepridil, and moxifloxacin).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.